19-norsteroidal-17-nitrates



United States Patent 3,352,891 l9-NORSTEROIDAL-17-NITRATES Gerhard R.Wendt, Havertown, and Kurt W. Ledig, Philadelphia, Pa., assignors toAmerican Home Products Corporation, New York, N.Y., acorporation ofDelaware No Drawing. Filed Feb. 11, 1966, Ser. No. 526,716 10 Claims.(Cl. 260-3974) This invention relates to new and useful nitrates of13-alkyl-l7,8-hydroxy-gon-4-en-3-ones having pharmacodynamic activity.

The novel compounds which are included within the scope of thisinvention are represented by the following formula ONOz R wherein R islower alkyl. Examples of such compounds includel-l7,8-hydroxyestr-4-en-3-0ne, nitrate; d-17/3-hy-.droxyestr-4-en-3-one, nitrate; anddl-13-ethyl-17fi-hydroxy-gon-4-en-3-one, nitrate.

The novel nitrates of the present invention may be prepared by thereaction of an appropriate l3-alkyl-17,8- hydroxy-gon-4-en-3-one, as aracemic mixture or as one of the component enantiomorphs, with a nitricacid-acetic anhydride mixture at temperatures below 0 C. When thereaction is complete, the excess acid is neutralized by the addition ofan alkaline reagent such as the hydroxide, carbonate or bicarbonate ofan alkali metal or alkaline earth metal salt. The 19-nor-steroidalnitrate is then separated and purified by conventional methods, such as,extraction and crystallization.

Many of the l9-nor-steroids employed as reactants in the above reactionare known compounds which are available from commercial sources, whilethe remainder can be prepared by the procedure described by H. Smith etal. in J. Chem. Soc. p. 4472 (1964). The l-estradiol-3- methyl etherstarting material of hereinafter Example I is prepared by the proceduredescribed in the copending application, U.S. Ser. No. 526,851, entitledChemical Resolution of gona-l,3,5(10),8,14-pentaen-17-ols, filed on Feb.11,1966.

In accord with the present invention, the new 19-norsteroidal nitratesherein described have been found to possess interesting pharmaceuticalproperties which render them useful as synthetic medicinals. Moreparticularly, these nitrates, in standard pharmacological tests, haveexhibited utility as vasodilators, lowering the arterial pressure by thedilation of the blood vessels.

When the 19-norsteroidal nitrates of this invention are employed asvasodilators, they may be administered alone or in combination withpharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules containing such excipients as starch, milk sugar, certain typesof clay and so forth. They may be administered sublingually in the formof troches or lozenges in which the active ingredient is mixed withsugar and corn syrups, flavoring agents and dyes; and then dehydratedsufiiciently to make it suitable for pressing into a solid form. Theymay be administered orally in the form of solutions which may containcoloring and flavoring agents or they may be injected paren- 3,352,89lPatented Nov. 14, 1967 ICC terally, that is intramuscularly,intravenously or subcutaneously. For parenteral administration they maybe used in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 0.1 mg. to about 20.0 mg. perkg. of body Weight per day, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 0.5mg. to about 10 mg. per kg. of body weight per day is most desirablyemployed in order to achieve effective results.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention, many variations of whichare possible without departing from the scope and spirit thereof.

Example I A solution of 250 ml. of 1,2dimethoxyethane, 250 ml. oftetrahydrofuran, 250 ml. of l-methoxy-Z-propanol, 1.1 liters of ammonia,and 4.2 g. of l-estradiol-3-methyl ether is treated with 4.2 g. oflithium. After the blue color disappears, the reaction mixture istreated with water and the crude (4.2 g.) l-3-methoxyestra-2,5-(10)-dien-l7/3-0l collected.

A suspension of ml. of methanol, 6 ml. of water, 8 ml. of conc.hydrochloric acid and 4.2 g. of above preparedl-3-methoxyestra-2,5(l0)-dien-l7fl-ol is stirred for 1 hour. The clearresulting solution is diluted with water and material collected withether to give after crystallization from ether/hexane, 1.4 g. ofproduce, M.P. 121.5-1225 C. After recrystallization from ether/hexanethere is obtained l-l7fi-hydroxyester-4-en-3-one, M.P. mas- 0., 06 57.6(CHC13); U.V. 241.5 m (16,740).

Analysis.for C H O Calcd: C, 78.79; H, 9.55. Found: C, 78.66; H, 9.25.

Acetic anhydride (9.4 ml.) is cooled to l5 C. and nitric acid (3.1 ml.of 95%) added dropwise at such a rate that the temperature did notexceed 6 C. The solution is cooled to 10 C. and 1.3 g. ofl-17B-hydroxyestr-4-ene-3-one is added with stirring. After 30 minutes,the reaction mixture is poured into ice-water, neutralized to pH 6 withsodium bicarbonate and the material extracted with ether. The organiclayer is concentrated and the resulting crystalline material collectedby filtration. In this manner, is obtained l-l7fi-hydroxyestr-4-en-3-one, nitrate, M.P. 1081l0 C.

Analysis.-f0r C H NO Calcd: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.72;H, 7.88; N, 4.17.

Example II To a mixture of 19 ml. of acetic anhydride and 6.5 ml. ofcone. nitric acid at 10 C, there is added with stirring 2.6 g. ofl-l3-ethyl-17fl-hydroxygon-4-en-3-one. After stirring for one-half hour,the reaction mixture is poured into ice-water, neutralized with sodiumhydroxide and 3. extracted with ether. Upon evaporation, there isobtained l-13-ethyl-17fi-hydroxygon-4-en-3-one nitrate.

Similarly, the nitrate of l-l7fi-hydroxy-13-propylgon 4-en-3-one isproduced.

Example 111 Nitric acid (6.2 ml., 95%) is slowly added to 18.8 ml. ofacetic anhydride at C. Subsequently, 2.6 g. ofzl-l-hydroxyestr-4-em3-one is added at -2OO C. and. the stirringreaction mixture is then gradually warmed to +2 C. within 20 minutes.The mixture is then poured over ice, neutralized with sodium bicarbonateand collected in either. The ether is concentrated and the crystallineresidue is d-l7 8-hydroxyestr-4-en-3-one, nitrate, M.P. 109-110 C.,

IR, 12.1 6.00 (conj. ketone); 6.20 (R-O-NOQ Analysis.for C18I I25NO4;Calcd.: C. 67.69; H, 7.89; N, 4.39. Found: C, 67.42;.H, 7.82; N, 4.43.

In a similar manner, d-l3-ethyl-l7fl-hydroxygon-4-en- 3-one, nitrate andd-175-hydroxy-13-propylgon-4-en-3- one, nitrate are obtained.

Example IV To a solution .of 21.7 ml. of acetic anhydride and 7.2 ml. offuming nitric acid at -40 C., there is added with stirring 3.0 g. ofdl-13-ethyl-17B-hydroxygon- 4-en-3-one and the reaction mixture broughtto 18 C. within a 25 min. period. The reaction mixture is poured intoice water, neutralized with sodium bicarbonate, extracted withchloroform and the combined extracts washed with 10% sodium carbonate.Evaporation of the solvent followed by recrystallization from ethylacetate yields 2.3 g. of a'l-l3-ethyl-17flwhydroxygon-4-en-3-one,nitrate, M.P. 141 C.,

QM; 6.05 (vs, conjugated C=0); 6.20 (vs, ON0

Analysis.-for C19H2'1N04, Calcd.: C, 68.44; H, 8.16; N,.4.20. Found: C,68.16; H, 7.99; N, 4.27.

Similarly, dl-17fi-hydroxy-l3-propylgon-4-en-3-one, nitrate;dl-13-butyl-17fi-hydroxygon-4 en-3-one, nitrate and dl 13 isobutyl-173-hydroxygon-4-en-3-one, nitrate are produced.

4 What is claimed is: 1. A compound selected from the group consistingof those having the formula:

wherein R is lower alkyl.

2. A compound as described in claim 1 which is l 17 3- hy-droxyestr 4 en3 one, nitrate.

3. A compound as described in claim 1 which is d 17!?- hydroxyestr 4 en3 one, nitrate.

4. A compound as described in claim 1 which is all 13- ethyl 17/3hydroxygon 4 en 3 one, nitrate.

5. A compound as described in claim 1 which is all- 176 hydroxy 13propylgon 4 en 3 one, nitrate.

6. A compound as described in claim 1 which is l 13- ethyl 17Bhydroxygon -.4 en 3 one, nitrate.

7. A compound as described in claim 1 which is d l3- ethyl 17,8hydroxygon 4 en 3 one, nitrate.

8. A compound as described in claim 1 which is a l- 13 butyl 17/3hydroxygon 4 en 3 one, nitrate.

9. A compound as described in claim 1 which is d!- 13 isobutyl 17Bhydroxygon 4 en 3 one, nitrate.

10. A compound as described in ,claim v1 which is lhydroxy 13 propylgon4 en 3 one, nitrate.

Legrand et al.: ,Compt. .Rend. Acad. Sci., 255, pages 2985 and 2986(1962).

LEWIS GOTTS, Primazy Examiner. T. M. MESHBESHER, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA: